Methamphetamine regulates stress-related neuropeptides via diverse epigenetic mechanisms

SUBRAMANIAM JAYANTHI; BETINA GONZALEZ; PAWARIS WONGPRAYOON; MICHAEL T. MCCOY; BRUCE LADENHEIM; ARTUR GODINO; JEAN LUD CADET

Chicago

Congreso; Neuroscience 2015; 2015

Society for Neuroscience

A single methamphetamine (METH) (10 mg/kg) dose caused time-dependent increases in stress-related neuropeptides, including Crh, Avp and Cartpt in the nucleus accumbens of rats. In general, gene transcription is regulated by complex epigenetic mechanisms that include covalent histone modifications or DNA methylation / hydroxymethylation. Here we show that METH significantly decreased DNA methylation at the CpG-rich sites near the promoter region of Crh and at CpG-rich intragenic sites of the Avp gene. METH caused no changes in DNA methylation but increased enrichment of pCREB on the Cartpt gene promoter. METH-induced hypomethylation is mediated via a cascade that includes DNA hydroxymethylation. METH was shown to increase DNA hydroxymethylation at the CpG-rich sequences located near the Crh TSS and at Avp intragenic sites. Because Ten-eleven translocation (TET) enzymes catalyze DNA hydroxymethylation, we conducted chromatin immunoprecipitation (ChIP) assay using TET1, TET2 and TET3 antibodies and found significant METH-induced increase of TET1 binding on the Crh promoter sequence and of TET3 binding on an Avp intragenic region. There were no changes in TET2 binding on Crh and Avp DNA sequences. Inhibition of TET activity using 1, 5-isoquinolinediol (ISO) blocked the METH-induced Crh and Avp mRNA expression. Together, these results show a potential role of TET in mediating METH-induced up-regulation of Crh and Avp mRNA expression in the nucleus accumbens. These observations hint to the possibility that METH can activate diverse regulatory epigenetic mechanisms to regulate gene expression in the brain.